Desflurane, 1,2,2.2-tetrafluoroethyl difluoromethyl ether (CF.sub.3 CHFOCHF.sub.2), is an inhalation anesthetic presently awaiting regulatory approval for marketing in the United States. The use of desflurane as an inhalation anesthetic is claimed in Terrell, U.S. Pat. No. 4,762,856, issued Aug. 9, 1988. Desflurane was originally disclosed in Example XXI of Russell et al U.S. Pat. No. 3,897,502, issued Jul. 29, 1975, which is directed to a method of fluorinating ethers to make compounds generally useful as solvents, degreasing agents and the like.
Desflurane has commercial potential as an inhalation anesthetic, particularly for outpatient procedures, because of its rapid rate of recovery and extremely low metabolism. As a result, there has been considerable effort devoted to finding an optimal synthesis therefor.
One method of preparing desflurane is by first converting fluoral methyl hemiacetal to 1,2,2,2-tetrafluoroethyl methyl ether (CF.sub.3 CHFOCH.sub.3) which is then chlorinated to produce a compound having the formula CF.sub.3 CHFOCHCl.sub.2. The resulting compound is fluorinated with HF in the presence of antimony pentachloride. See, for example, German Offen. 2,361,058 (1975). This is a complex, expensive process which is not suited to industrial scale.
More recently, a number of processes for preparing desflurane have been patented. Halpern et al, U.S. Pat. No. 4,855,511, issued Aug. 8, 1989. discloses preparing desflurane by the reaction of a compound having the formula CHCl.sub.2 OCHClCOCl with sulfur tetrafluoride at elevated temperatures. Halpern et al, U.S. Pat. No. 4,874,901, issued Oct. 17, 1989, discloses a method of fluorinating a chlorine on the carbon adjacent the ether oxygen in chloro-fluoro ethers by reaction with sodium or potassium fluoride at elevated temperature and pressure in the absence of solvent. By this method, isoflurane (CF.sub.3 CHClOCHF.sub.2) is converted to desflurane.
In Robin et al, U.S. Pat. No. 4,972,040, issued Nov. 20, 1990, fluoral methyl hemiacetal, CF.sub.3 CH(OH)OCH.sub.3, is reacted with p-toluene sulfonyl chloride to form the corresponding tosylate compound. The tosylate group is then removed by reaction with a fluorinating agent to form CF.sub.3 CHFOCH.sub.3. This compound is converted to desflurane by chlorinating the methyl group, preferably with chlorine gas, followed by reaction with a fluorinating agent.
Robin et al. U.S. Pat. No. 5,015,781, issued May 14, 1991, disclosed a process for forming desflurane by the direct fluorination of isoflurane (CF.sub.3 CHClOCHF.sub.2) by bromine trifluoride. Cicco, U.S. Pat. No. 5,026,924, issued Jun. 25, 1991, discloses a low temperature preparation of desflurane comprising reacting isoflurane with hydrogen fluoride in the presence of a catalyst comprising antimony pentachloride, alone or in combination with antimony trichloride.
These methods, although adequate, can be improved upon with regard to a number of particulars. The synthesis utilizing sulfur tetrafluoride, for example is disadvantageous because it is not commercially available and is considered very toxic. The processes wherein desflurane is formed from isoflurane are disadvantageous in that the preparation of isoflurane according to the following reaction EQU CF.sub.3 CH.sub.2 OH+CF.sub.2 ClH+NaOH.fwdarw.CF.sub.3 CH.sub.2 OCF.sub.2 H EQU CF.sub.3 CH.sub.2 OCF.sub.2 H+1/2Cl.sub.2 .fwdarw.CF.sub.3 CHClOCF.sub.3 H+HCl
utilizes trifluoroethanol which is expensive and chlorodifluoromethane which is not considered favorable to the environment.
Accordingly, there exists a need for a synthesis of desflurane which is efficient, utilizes relatively inexpensive starting materials, and is environmentally acceptable. Such a process is provided in accordance with the present invention.